Composite containing poly(glycerol sebacate) filler

ABSTRACT

A filler material of a thermoset resin of a diacid/polyol, such as PGS is provided. The filler useful in forming composites, such as those in which the filler and a resin matrix are of the same material to provide a homogenous polymeric composition. Composites in which at least one of the matrix, the filler or both are PGS are also provided. Methods of forming such filler materials and composites are also disclosed. The composites allow extrusion process to form articles from materials that would not otherwise be capable of being extruded.

RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 15/442,055 filed Feb. 24, 2017, which claims the benefit of, andpriority to, U.S. App. No. 62/299,595 filed Feb. 25, 2016, both of whichare hereby incorporated by reference in their entirety.

FIELD

This application relates to composites and more particularly tocomposites that include glycerol/sebacic acid polymeric filler and tothe filler itself.

BACKGROUND

Polymers of glycerol/sebacic acid (PGS), including both homopolymers andcopolymers, have been shown to hold great promise as a bioresorbablematerial for use in medical and other applications. However, PGS hassome material drawbacks that have limited potential commercialprocessing. PGS has a melt temperature of ˜35° C. and the curing processto produce the thermoset elastomer requires temperatures above 100° C.Therefore, to produce structures with a defined form a mold is requiredduring the cure process. This limits the potential applications andworkable structures of thermoset PGS.

Extrusion is a more desirable way to form shaped goods, but pure PGScannot be readily extruded due to its low viscosity, non-ideal thermalproperties, and long cure times. In order to extrude PGS, it must softenat elevated temperatures to be processed through a dye, outputting astructure that can withstand physiological and/or curing temperatures.Accordingly, extrusion techniques such as electrospinning proveunsatisfactory as it requires co-blending and/or a solvent basedextrusion process. In addition, the electrospinning process producesrandom fiber orientations as opposed to extrusion which producesoriented structures that can be non-fibrous.

SUMMARY

According to an exemplary embodiment, a filler material comprises athermoset resin of a polymer comprising a condensation reaction productof a diacid and a polyol, the filler material having a particle sizebetween 0.5 and 1000 microns. In some embodiments, the filler materialcomprises PGS.

According to another exemplary embodiment, an article comprises acomposite of a resin matrix and a thermoset filler, the thermoset fillerhaving a particle size between 0.5 and 1000 microns in which the resinmatrix, thermoset filler, or both of the resin matrix and thermosetfiller comprise PGS and the thermoset filler is present as about 10% byweight to about 90% by weight of the composite.

According to one exemplary embodiment, an article comprises a compositeof a thermoset filler having a particle size less than 250 microns in across-linked resin matrix in which the resin matrix and thermoset fillerboth comprise PGS, the thermoset filler is present from about 40% byweight to about 70% by weight of the composite, the resin matrix has amolecular weight of 5,000-50,000 Da. prior to cross-linking, thethermoset filler has a cross-link density of cross-link density of about0.07 mol/L or greater, and the thermoset filler and the resin matrixeach have a molar ratio of glycerol to sebacic acid in the range of0.7:1 to 1.3:1.

According to another exemplary embodiment, an article comprises acomposite of a resin matrix and a thermoset filler, the thermoset fillerhaving a particle size between 0.5 and 1000 microns in which the resinmatrix and the thermoset filler both comprise the same material, thethermoset filler being present as about 10% by weight to about 90% byweight of the composite.

According to another exemplary embodiment, a method of forming a fillermaterial comprises providing a thermoset comprising PGS and formingparticles of the thermoset material having a particle size between 0.5and 1000 microns.

According to another exemplary embodiment, a method of forming anarticle comprises providing a composite comprising a PGS resin matrixand a thermoset PGS filler material having a particle size between 0.5and 1000 microns, wherein the thermoset PGS filler material is at least50% by weight of the composite; forming the composite into apredetermined shape; and curing the PGS resin matrix.

Among the advantages of exemplary embodiments are that it has beendiscovered that with the use of a fine thermoset PGS filler, compositestructures can be formed and crosslinked without the need for a mold.

Another advantage is that a composite is provided that includes a matrixand thermoset filler of the same molecular formula, which allowsextrusion and other processing of materials that could not beaccomplished by the neat resin alone while providing an ability tomaintain an article still having an overall homogenous composition.

Another advantage is that PGS resin mixed with PGS filler holds itsstructure at 37° C. and therefore does not need further processing athigh temperatures once the desired structure is formed, but it can stillbe crosslinked to create a more mechanically stable structure.

Yet another advantage is that composites of PGS resin and PGS filler canbe extruded into shapes that hold their geometries at 37° C. and undercuring at temperatures above 100° C.

Still another advantage is that in addition to overcoming processdifficulties, the ability to extrude PGS in a composite form inaccordance with exemplary embodiments opens the potential use of thismaterial to a wider variety of applications, including 3D printing andother additive manufacturing techniques, as well as a wide variety ofmedical and industrial uses.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

Exemplary embodiments are directed to a thermoset PGS filler as well ascomposites formed using the PGS filler and methods and products relatedto the same. PGS filler is sometimes referred to herein as a PGS flouror PGS powder.

As used herein, “composite” broadly refers to any combination of a resinand filler material and includes both low and high solids compositionswhich may be used to form a bulk solid or in coating and filmapplications, the filler acting as a vehicle-binder adjunct or sole bulkresin to the base formulation. In other embodiments, the filler behavesas an additive with controlled “oil absorption coefficient” action basedon particle size such that “wet formulation additives” can adsorb withinthe filler particles; that is, the filler particles provide a wettingsurface to mop up fluid phased additives.

Although described primarily herein with respect to PGS, it will beappreciated that any polymer formed from a multi-functional acid monomerand a polyol monomer capable of forming a thermoset may be employed forforming the filler material. Accordingly, in certain aspects of theinvention, the polymer is a condensation reaction product of glycerol orother alcohol monomer and a diacid having the formula[HOOC(CH₂)_(n)COOH], wherein n=1-30, including malonic acid, succinicacid, glutaric acid, adipic acid, pimelic acid, suberic acid, andazelaic acid as well as sebacic acid.

Furthermore, although primarily discussed herein with respect to PGS asa preferred resin of the composite, the resins used for the matrix ofthe composites formed in accordance with exemplary embodiments are notso limited and may be any polymeric material, but preferably arebiocompatible and erodible/degradable. Exemplary resins in addition toPGS include a polymer containing glycerol and sebacic acid of varyinginitial molar ratios, condensation polymers of a diacid (such as thosediscussed previously) and a polyol, polycaprolactone (PCL), polylacticacid (PLA), polyglycolide (PGA), and poly(glycolide-co-lactide) (PLGA),poly(propylene fumarate), poly(ether esters) such as polydioxanone,poly(ortho esters), polyanhydrides, polycarbonates and co-polymers andblends thereof, as well as suitable urethanes and acrylates. Othersuitable resin materials for the matrix include biologics such as, butnot limited to, collagen, gelatin, polysaccharides, alginate,glycosaminoglycans, proteoglycans, chitosan and chitin, agarose, etc.,which may be used in combination together with and/or blended with oneor more of the synthetic resins in the matrix.

According to some presently preferred embodiments, the composite isformed of a resin and a thermoset filler having the same chemistry.

The matrix resin should be able to flow or soften at a given temperatureto allow for particle integration. Particularly in the case where theresin is PGS, the PGS resin has a molecular weight in the range of5,000-50,000 Da; in some embodiments, the PGS resin has a molecularweight in the range of 15,000-25,000 Da. References herein to molecularweight refer to weight average molecular weight.

The matrix may be composed entirely of the polymer resin or may includeone or more additional components. In some embodiments, the matrixcontains one or more drugs, medicaments, or other biologically and/orpharmaceutically active ingredients which may be incorporated thereinfor controlled release during subsequent resorption or degradation ofthe matrix due to PGS' surface eroding characteristics.

The filler of the composites in accordance with exemplary embodimentscomprises thermoset PGS (or other polymer of a diacid and polyol) thathas been processed into a flour or powder of fine particle size (e.g.,less than 1000 microns). The PGS thermoset filler cross-link density isabout 0.07 mol/L or greater, which is calculated with respect to thethermoset material prior to particularization by soaking samples intetrahydrofuran for 24 hours to obtain a swollen mass, dried until aconstant dry mass is acquired (typically about 3 days) and the swellingpercentage is then used to calculate the crosslink density using theFlory-Rehner expression for tetra-functional affine networks.

The success of using PGS as a filler material was unexpected andsurprising; PGS is a soft elastomer and thus would not ordinarily beconsidered a suitable filler material in many applications, particularlyfor dispersion within a matrix comprising PGS resin to form a compositethat demonstrates significant differences in rheology and improvedhandling and processing characteristics over either neat PGS resin orneat thermoset PGS alone.

Other materials, both organic and inorganic, may be used in combinationwith PGS flour as an additional filler material for forming compositesin accordance with exemplary embodiments and include particles ofcollagen, inorganic salts (e.g. calcium phosphate, titanium dioxide),gelatin, PCL, PGLA, PGA and PLA, all by way of example only. Even ifother fillers are used, the PGS filler should remain the primary fillercomponent to create a stable composite with a rheology that can maintainits structure at physiological 37° C., as well as at curing temperaturesabove 100° C.

Filler particle size may vary depending on application, but the filleris generally between 0.5 and 1000 microns and typically less than 850microns. Smaller particle sizes are generally preferred for additivemanufacturing and traditional Brabender or fiber extrusion machines,with comparatively larger sizes being able to be used for industrial,orthopedic, wound care and dental applications. In some embodiments,maximum particle size is about 60 to 125 microns for additivemanufacturing, while maximum particle size for other forms of extrusionis typically in the range of about 75 to about 300 microns, such asabout 175 to about 250 microns.

The thermoset filler can be manufactured by any suitable method offorming fine particles of thermoset material.

In one embodiment, thermoset PGS is processed into filler particles bycryogrinding. In this process, a sheet or other larger mass of thermosetPGS is frozen to very low temperatures, e.g. direct exposure to liquidnitrogen. This renders the PGS thermoset brittle enough to be groundinto small granules while in its frozen state. The thus-formed fillerparticles resume their elastomeric state upon returning to ambienttemperature after completion of the process. Cryogrinding may be mostuseful when filler particles having smaller diameters (e.g. about 300microns or less) are desired.

In another embodiment, the filler particles are formed through anextraction and milling technique. PGS can be analogized to a sol-gel,with higher molecular weight chains acting as the gel and lowermolecular weight chains acting as the connective sol. When thermoset PGSis soaked in an organic solvent, some sol portions are removed, whichresults in an unstable structure of gel portions capable of being groundinto a fine powder.

In the extraction process of PGS filler manufacture, thermoset PGS issoaked in an organic solvent (such as ethyl acetate or THF) whichdissolves a portion of the low molecular weight fractions of the PGS.This weakens the overall thermoset structure and allows it to crumblewhen agitated, such as with a dual-asymmetric centrifuge mixer,resulting in a fluffy powder-like material.

In some embodiments, ethyl acetate is a preferred organic solvent, as ithas demonstrated better selectivity in dissolving low molecular weightfractions. Other organic solvents, such as THF, may also be used but cantend to also pull out some higher molecular weight fractions. Theremoval of some higher molecular weight fractions may be desired in somecases to produce smaller particle sizes. Particle size can be controlledbased on solvent soak time, with longer soaks and/or removal of highermolecular weight fractions resulting in smaller particle sizes, as wellas the glycerol to sebacic acid molar ratio used in the polymerizationof PGS.

Regardless of the technique used, the resulting filler particles canthen be further sized, for example, by sieving or other sizingtechniques. The PGS filler particles are observed to be cohesive andtend to agglomerate. Accordingly, in some embodiments the fillerparticles can be wetted with ethyl acetate to reduce particleinteraction as well as provide additional weight. Hydroxyapatite canalso be used to prevent particle interactions by coating the particles,minimizing any interactions and resulting in a fine powder. In anotherembodiment, sizing may occur while the particles are in a harder, frozenstate, such as under the presence of liquid nitrogen.

The molar ratio of glycerol:sebacic acid in the thermoset PGS used forthe filler material may vary, but typically is in the range of 0.7:1 to1.3:1. Reducing the amount of glycerol relative to the amount of sebacicacid produces a larger amount of finer particle sizes during fillerparticle production using the extraction method due to a smallerpercentage of sol holding the structure together. However, higheramounts of glycerol, for example, up to 1.3:1 glycerol:sebacic acid, isalso suitable, with a preference in some embodiments for a 1:1 molarratio. While the stoichiometric ratios of glycerol to sebacic acid canbe varied for the PGS particles, the particles should still be of asurface energy similar to that of the resin matrix. In some embodiments,that is accomplished by providing the PGS filler particles having amolar ratio of glycerol:sebacic acid that is similar or the same as thatof the resin in the matrix. In a presently preferred embodiment, acomposite includes a PGS thermoset filler made from 1:1 glycerol:sebacicacid molar ratio dispersed in a PGS resin matrix that also has a 1:1glycerol:sebacic acid molar ratio.

Like the matrix material, the polymeric material used to form the fillerparticles may be doped with an active ingredient.

The filler particles are added to the resin matrix to form a composite.The weight percentage of filler in the composite may vary widely basedon numerous factors, including the intended end use application.Generally, the composite is about 10% by weight to about 90% by weightfiller. In some embodiments, the composite is about 40% by weight toabout 70% by weight filler for extrusion applications, preferably atleast 50% by weight or more filler (for 75-250 μm particles), in orderfor the composite to hold its shape. It has been observed that higherratios of filler result in increases in peak load of the final curedcomposite and enhanced mechanical integrity in the uncured composite.Further as previously noted, to the extent that the filler particlesinclude multiple different materials, the filler should be primarily theparticulate thermoset material, which is preferably of the samecomposition used as the resin matrix.

By outward appearances, the composite appears to cure at roomtemperature, as the composite hardens and does not exhibit the tackinessor stickiness associated with uncured PGS resin at that temperature.Despite the appearance, analysis by differential scanning calorimetryreflects that the composite does not cure at room temperature, althoughit does suggest the filler influences the crystallization temperature ofthe resin, shifting it lower. While the filler does not apparently alterthe cure itself, it does render a composite that is capable of holdingits shape and which can be readily handled. While not wishing to bebound by theory, it is believed that some of the morphology changesresult from the filler particles absorbing or adsorbing the uncuredresin of the composite.

The composite can be processed and shaped in any desired fashion,including by extrusion into tubes, fibers, or other devices and/or as anink for use in additive manufacturing. In some cases, the composite maybe compounded and/or co-extruded with other polymeric materials.

Once the desired shape is formed, the composite can be cured into thefinal product without the use of a mold. Curing the composite (i.e.,curing the resin matrix of the composite) typically takes place attemperatures in excess of 100° C. under pressures less than atmosphericpressure and results in a final product formed of the compositematerial. In some embodiments, the curing step may also involveannealing. In some embodiments, the composite is cured at a temperatureof about 90° C. to about 150° C. at a pressure in the range of about 5torr to about 20 torr for a period of about 4 hours to about 96 hours.

Like neat PGS, a PGS/PGS composite has a controlled release due tosurface erosion of both the resin matrix and thermoset particles. Theresin and thermoset particles of the composite have different crosslinkdensities and, as a result, degrade at two different rates. in vitrodegradation studies of different PGS/PGS composite structures closelymimicked cast PGS thermosets with an initial bolus degradation, followedby a linear decrease in mass loss over time. Surface erosion was alsoconfirmed by surface topography analysis over time, as well as inherentpore formation limited to the surface. in vivo, composites in accordancewith exemplary embodiments may form a porous network in real time as theresin portion of the composite degrades faster than the thermosetparticles allowing for cellular infiltration into the compositestructure.

Like neat PGS, exemplary embodiments also exhibit antimicrobial activityand composites can be used in suitable applications for that purpose. Inone embodiment, the composite is a delivery vehicle for controlledrelease or dual controlled release whereby the degradative action of thepolymer of the composite releases an included (by formulation) bioactivematerial with a specified or tailored release profile, as well as theunderlying antimicrobial degradation products of the PGS componentsthemselves.

Exemplary embodiments may be employed in any situation for which it isdesirable to provide a resorbable composite polymer with antimicrobialbenefits. Exemplary applications include agriculture; construction;water management; surface preservation; architectural preservation;anti-fouling; environmental barriers; wound healing fabric surfaces,treatments, coatings, and controlled release vehicles; food additive;biomedical device coating/adhesive/sheets or films for implant deviceprophylactic peri-operative post-surgical infection control; temporarybarriers; any surface where microbial colonization threatens humanhealth or condition; hydrophilic agents; textile treatments; veterinary;wound care; biofilm control; regenerative engineering without antibioticneed; surface protection|sanitization; water management; filtration;fabric coating for protection; implantable textiles; prophylacticprosthetic implant coatings; conformal coatings; cosmetics; OTC pharma;and aquaculture, all by way of example only.

PGS composites in accordance with exemplary embodiments can beintegrated into a wide variety of textile structures. Textile structurescan be made from monofilament or multifilament yarn comprising, withoutlimitation, polylactides and polyglycolides and their copolymers,polydioxanone, polytrimethylene carbonate, polycaprolactone,polyethylene terephthalate, low to ultra-high molecular weightpolyethylene, polypropylene, polyamides, silk, andpolytetrafluoroethylene. Cured tube or rod composites of varying sizescan be placed on mandrels and braided over. Uncured composite sheets canalso be softened using higher temperatures and laminated with meshes ofdifferent polymer types and constructions using a die press,3-roll-stack, or other laminating techniques. These laminated sheets canthen be cured to form one cohesive structure that is unable to bedelaminated. PGS composites can also be co-extruded with textilestructures that nullify the need for a subsequent lamination step. PGScomposites reinforced with textiles can be constructed into medicaldevices for use as, but not limited to, cardiovascular patch, cardiacpatch, pericardial patch, cardiac support mesh wrap, vessel guard,vascular graft, shunt, adhesion barrier, dural substitute, nerveconduit, heart valve, pacemaker mesh bag, tympanostomy tube,annuloplasty ring, meniscal scaffold, bone sheath or wrap, tendon wrap,surgical film, or surgical mesh.

Among the applications for which exemplary embodiments of the inventionmay be employed include a wide variety of medical and industrialapplications. In some embodiments, the composite may be used in thecreation of an implant, or as a lubricant or coating on implants orother devices used in orthopedic, neural, and cardiovascularapplications, for example. Other medical applications include use inwound care such as the formation of a composite of a collagen flour(e.g. Avitene) and PGS thermoset filler to form a hydrogel, bone puttycomposites (PGS resin, calcium phosphate and PGS thermoset filler), andbone plugs formed of cured putty cut to a variety of different sizes.

Still other medical applications include a vehicle for delivery ofsubstances by subcutaneous injection, two-part drug delivery, and as aporogen, all by way of example.

Industrial applications include use in degradable paints and inks; foodprocessing to deliver flavor or vitamins; water treatment such as forcontrolled release of algaecide, pesticide or other treatments; or evenas delayed release fish food, again all by way of example.

EXAMPLES

The invention is further described with respect to the followingexamples which are presented by way of exemplification and notlimitation.

Example 1

PGS/PGS composites were formed by using a PGS thermoset filler added toa PGS resin at various loading levels. The filler was created by theextraction method described herein starting with a PGS thermoset havinga cross-link density greater than 0.100 mol/L (prior to particleformation) to provide a PGS thermoset filler having an average particlesize less than 212 μm. The filler was added into a PGS resin (MW 12,625,PDI 7.044), in amounts of 50%, 60% and 70% by weight, and pressed into a1 mm film followed by curing at 20 hours at 120° C. at a pressure of 10torr.

Tensile testing of the resulting specimens was conducted and reflectedthat increasing filler concentration led to an observed increase ofYoung's Module (up to 800 kPa) and a decreased strain at break from 0.5to 0.3. The composites also showed an increased suture strength comparedto a cast film of neat PGS. While suture strength of cast films istypically less than 1.5N, the lowest suture strength observed for thecured PGS composites of Example 1 was almost 50% higher at 2.2N.

Example 2

To explore applicability for orthopedic applications, PGS fillers (<212μm particle size, MW 21,597 of resin prior crosslinking, cross-linkdensity greater than 0.100 mol/L and glycerol:sebacic acid ratio (1:1))were mixed with varying amounts (3%-25% wt) of hydroxyapatite (HA),which formed finely coated, discrete PGS filler particles. Composites ofPGS filler, PGS resin (also having a 1:1 glycerol:sebacic acid ratio)and a calcium phosphate filler (including hydroxyapatite (HA) andβ-Tricalcium phosphate (TCP)) were formed into a moldable paste.

A variety of composites were formed including: Ex. 2a.: 30% wt PGS flour(212-850 μm), 30% wt HA and 40% wt PGS resin; Ex. 2b.: 35% wt PGS flour(<212 μm), 20% wt HA and 45% wt PGS resin; Ex. 2c.: 50% wt. PGS flour(212-850 μm), 30% wt TCP and 20% PGS resin; and Ex. 2d.: 40% wt PGSflour (<212 μm), 30% wt TCP and 30% wt PGS resin.

Example 3

PGS/PGS composites of different weight ratios were extruded through a965 μm nozzle with a dispenser to explore applicability for 3D printingapplications. Compositions with a 40% wt filler concentration showed themost promise, with a structure that was fairly maintained after curing;those at less than 40% by weight did not hold their shape well; those inexcess of 40% wt, up to 70% wt, provided suitable in maintainingstructure but with increasing viscosity and slower to extrude. Fillerparticles can be pre-wetted with glycerol or oil to minimize thehardening and subsequent extrusion difficulties associated.

Example 4

Vitamin B₁₂ was loaded at 3% w/w concentration into PGS resin. Thematerial was cured at 120° C. for 48 hours. The resulting thermoset wasformed into filler particles by the extraction method. Approximately 100mg of the particles were placed into multiple vials and soaked inphosphate buffered saline (PBS) of pH=7.4. At predetermined incubationtimes the PBS of the samples was tested by UV/Vis to determine theamount of Vitamin Biz released, and the mass loss of the sample was alsodetermined. The rate of vitamin Biz release and mass loss both exhibiteda linear trend (5.95 μg/day and 0.16%/day respectively), indicating thefiller exhibits controlled release properties due to its surfacedegradation mechanism.

To demonstrate a 2-part controlled release mechanism for actives,curcumin-doped PGS flour particles were combined with PGS resin(containing 5% w/w Vitamin B₁₂) in a 60:40 ratio by mixing 200 g of thedoped resin with 300 g of the doped flour particles to create acomposite. The glycerol:sebacic acid molar ratio for each of the flourparticles and the resin matrix was 1:1. Samples were cured at 120° C.and 10 Torr for a 15 hour period and cut into 1 mm wafers. The sampleswere placed into individual vials and soaked in phosphate bufferedsaline (PBS) of pH=7.4. At predetermined incubation times the PBS of thesamples was tested by UV/Vis to determine the amount of Vitamin B₁₂ andcurcumin released. Results demonstrated zero-order release of both B₁₂(1.2%/day) and curcumin (0.12%/day) at different rates. The twodifferent linear release rates are due to the difference in crosslinkdensity between the resin portion (lower crosslink density) of thecomposite and the flour particles (higher crosslink density).

Example 5

A 1 mm PGS thermoset was made by casting and curing molten PGS in amold, which took approximately 72 hours to cure. A PGS/PGS composite(60% wt. PGS flour to 40% wt. PGS resin—each of a 1:1 glycerol:sebacicacid molar ratio) of the same size was manually formed into a blockwithout a mold and held its shape during curing. This exhibited a fullcure in 15 hours, illustrating the same final dimension of PGS inthermoset form can be manufactured in less than half the time with thePGS/PGS composite compared to the PGS resin. This is believed to atleast partly result from the decreased PGS resin present in the PGS/PGScomposite. The PGS resin appears to thinly coat the thermoset fillerparticles, with the thin PGS resin film curing faster than a thick layerof PGS resin.

Example 6

A PGS flour/PGS resin 60/40 w/w ratio (each a 1:1 molar ratio ofglycerol:sebacic acid) was injected into a Brabender at 10 mL/min with asyringe pump. After approximately 50 g of material had traveled throughthe screw, a hollow tube was successfully extruded through a 0.5 inchOD×0.25 inch ID tube die. The same composite was successfully extrudedin the same manner through a 0.375 inch OD×0.125 inch ID tube die. Aselect amount of the tubing was cured in the oven at 120° C. and 10 Torrfor approximately 16 hours. The tube held its shape in the oven and theinner wall thickness showed minimal change.

This same PGS flour/PGS resin 60/40 w/w ratio was injected with an aircylinder into the Brabender and extruded into a variety of shapes/sizesusing different dies. Sheets, tubes and rods were all successfullyextruded on a commercial scale, with types and sizes of materialsoutlined in Table 1. All shapes were further processed by curing in avacuum oven at 120° C., 10 torr for a minimum of 15 hours and a maximumof 48 hours. Shapes maintained their structure through the curingprocess.

TABLE 1 Sheet Tube Rod  1 mm 2.5 mm OD, 1.5 mm ID 1 mm dia 500 μm 3 mmOD, 2 mm ID 3 mm dia 5 mm OD, 3 mm ID ¼″OD, ⅛″ ID 9 mm OD, 6 mm ID ⅜″OD,¼″ ID

Example 7

Porous structures were also achieved with a salt leaching technique. A55/45 PGS flour/resin ratio and 2:1 salt:resin of salt/PGS resin/PGSflour mixture was injected into the Brabender twin screw extruder andprocessed like the neat composite structures. A salt composite 1 mmsheet and ⅜″ OD ⅛″ ID tube have successfully been extruded, cured andthen soaked in water to remove salt leaving open pores.

Example 8

Calcium chloride, sodium chloride and PGS flour were processed to obtainparticles having an average particle size less than 106 μm. A 50% byweight filler to PGS resin composite was mixed and formed into a sphere.The spheres were cured at 120° C. and 10 Torr for approximately 16hours. Among the different fillers of the same particle size, thePGS/PGS composite was the only one to maintain the spherical shape.Through SEM imaging, PGS filler particles were fully integrated, whileNaCl particles appeared to repel the PGS and CaCl₂ appeared to havecoated the outer surface of the particle suggesting that particle sizealone is not sufficient for composite formation and that chemicalcompatibility between resin matrix and flour is necessary for successfulcomposite formation.

Example 9

PGS filler particle size was varied (<212 μm, 212-850 μm, and 1-2 mm)and used to make 60% by weight PGS filler to PGS resin composites.Rheology of the uncured composites showed similar LVE ranges, indicatingstable structures. The samples were cured into spheres, in which onlythe smallest PGS flour particles (e.g. <212 μm) maintained a sphericalshape. However, all PGS/PGS composites were homogeneous and flexiblestructures. A 400 μm gelatin/PGS resin composite of the same ratio wasalso constructed; it's rheology showed a very short LVE range,representative of an unstable structure. After curing, the hard, brittlegelatin/PGS composite did not maintain its shape.

Example 10

PGS/PGS composite extruded tubes of sizes 0.25 inch OD, 0.125 inch IDand 3 mm OD, 2 mm ID were placed onto an appropriate sized mandrel andassembled to be fed into a braider. PGA fiber was used to create a braidover top of the extruded tubes and suture retention of the structureincreased. PGS/PGS composites were also incorporated into textiles bylaminating using mild temperatures and a press to secure uncuredextruded sheet onto low and high porosity meshes made from PET, PGA, andPP.

Example 11

PGS composites were tested for antimicrobial activity and efficacyagainst Pseudomonas aeruginosa and Staphylococcus aureus. Surfaces ofPGS composites were inoculated with bacteria and compared againstpolypropylene controls. After a 24-hour incubation time, PGS compositesdemonstrated >6.38 and >5.80 log reduction against Pseudomonasaeruginosa and Staphylococcus aureus which equates to >99.99996%and >99.9998% reduction in bacterial counts, respectively.

Example 12

PGS flour particles of <212 um size were formulated with a gelatin PGSmixture as described in U.S. Pub. No. 20160046832 in a 60:40 ratio bymass using dual-asymmetric centrifuge mixing. The resultant compositewas pressed into a 1 mm film and lyophilized for a 16-hour period. Thelyophilized film exhibited good mechanical strength and was porous. Thefilm was then further processed in a vacuum oven at 120° C. and 10 Torrfor a 15-hour period to produce a film that could withstand aqueous invivo conditions. Such a film could act as a wound care dressing or softtissue filler.

Example 13

PGS flour/resin (60/40 wt./wt.) were extruded into 3 mm rod; 0.25 inchOD, 0.125 inch ID tube; and 1 mm sheet. Samples were cured for 15 or 24hours. Once cured, samples were cut to 2″ length (tube and rod) or ASTMD638-V dog-bone (sheet). Samples were soaked in 0.05M PBS at pH=7.4 and37.0° C. for predetermined amounts of time. Samples were analyzed formass loss, changes in surface morphology (SEM), and mechanical strength(rod and sheet for tensile, tube for compression) over time. All threesample types showed a linear relationship (R² values >0.99) between massloss and degradation rate, indicating they degrade by surface erosion.Furthermore, mechanical testing showed a linear loss of mechanicalstrength, whether tensile or compression, over time. Scanning electronmicroscopy revealed the formation of pores over time that are limited tothe surface of the sample, further indicating the sample degrade bysurface erosion. These results verify that PGS/PGS composites maintainthe surface erosion characteristic of a neat, homogenous PGS material.

Example 14

A 60/40 w/w flour to resin extruded 1 mm sheet composite was tested inan intramuscular in vivo rabbit model. Twelve female New Zealand Whiterabbits underwent anesthesia to expose the paravertebral muscle. Threepockets per animal were formed between the muscle fibers. Gammasterilized 10×1×1 mm composite, steam sterilized 10×1×mm high densitypolyethylene (HDPE) (negative control) and 10 mm long Vicryl PGA suture(positive control) were implanted into the pockets along with locationmarkers. The fascia was closed with nonabsorbable suture and the skinwas closed with stainless steel wound clips. Animals were housed in anAAALAC International accredited facility and room temperature, relativehumidity, light cycle, and general health were maintained/observeddaily.

At 2, 4, 8 and 16 weeks after implantation, three animals werearbitrarily selected, euthanized and paravertebral muscles weredissected and fixed in buffered formalin. The composite test articleshowed near complete or complete degradation at weeks 4, 8 and 16. Itwas a slight irritant compared to HDPE at week 2, and a non-irritantcompared to HDPE at weeks 4, 8 and 16. Compared to the Vicryl PGAsuture, the PGS composite was a non-irritant at all time points.

Example 15

A poly(glycerol sebacate) urethane (PGSU) was produced by reacting anoligomeric form of PGS with HDI in a ratio of 1:1 HDI:free hydroxyl.Resultant material was a thermoset urethane. Material was to ground toachieve sub-212 micron particles using a dual-asymmetric centrifugalmixer. PGSU flour particles resembled standard PGS flour particles interms of consistency and particle shape. PGSU flour particles could beformulated with PGS resin in a 60/40 flour/resin ratio to obtain astable composite.

While certain embodiments of the present invention have been describedand/or exemplified above, various other embodiments will be apparent tothose skilled in the art from the foregoing disclosure. The presentinvention is, therefore, not limited to the particular embodimentsdescribed and/or exemplified, but is capable of considerable variationand modification without departure from the scope and spirit of theappended claims.

Moreover, as used herein, the term “about” means that dimensions, sizes,formulations, parameters, shapes and other quantities andcharacteristics are not and need not be exact, but may be approximateand/or larger or smaller, as desired, reflecting tolerances, conversionfactors, rounding off, measurement error and the like, and other factorsknown to those of skill in the art. In general, a dimension, size,formulation, parameter, shape or other quantity or characteristic is“about” or “approximate” whether or not expressly stated to be such. Itis noted that embodiments of very different sizes, shapes and dimensionsmay employ the described arrangements.

Furthermore, the transitional terms “comprising”, “consistingessentially of” and “consisting of”, when used in the appended claims,in original and amended form, define the claim scope with respect towhat unrecited additional claim elements or steps, if any, are excludedfrom the scope of the claim(s). The term “comprising” is intended to beinclusive or open-ended and does not exclude any additional, unrecitedelement, method, step or material. The term “consisting of” excludes anyelement, step or material other than those specified in the claim and,in the latter instance, impurities ordinary associated with thespecified material(s). The term “consisting essentially of” limits thescope of a claim to the specified elements, steps or material(s) andthose that do not materially affect the basic and novelcharacteristic(s) of the claimed invention. All materials and methodsdescribed herein that embody the present invention can, in alternateembodiments, be more specifically defined by any of the transitionalterms “comprising,” “consisting essentially of,” and consisting of.”

What is claimed is:
 1. A filler material comprising particles of athermoset resin of a polymer that comprises a condensation reactionproduct of a diacid and a polyol and having a particle size between 0.5and 1000 microns.
 2. The filler material of claim 1, having a particlesize between 0.5 and 300 microns.
 3. The filler material of claim 1,wherein the filler material is a thermoset resin of polymer ofglycerol/sebacic acid (PGS).
 4. The filler material of claim 3, whereinthe PGS has a molar ratio of glycerol to sebacic acid in the range of0.7:1 to 1.3:1.
 5. The filler material of claim 4, wherein the PGS has amolar ratio of glycerol to sebacic acid of 1:1.
 6. The filler materialof claim 3, wherein the PGS has a cross-link density of about 0.07 mol/Lor greater.
 7. The filler material of claim 1, wherein the thermosetresin is doped with an active ingredient.
 8. A method of forming afiller material, the method comprising: providing a thermoset materialcomprising polymer of glycerol/sebacic acid (PGS); and forming particlesof the thermoset material having a particle size between 0.5 and 1000microns.
 9. The method of claim 8, wherein the step of forming comprisescryogrinding the thermoset material.
 10. The method of claim 9, whereinthe particles of the thermoset material have a particle size between 0.5and 300 microns.
 11. The method of claim 8, wherein the step of formingcomprises soaking the thermoset material in a solvent to dissolve lowmolecular weight fractions and thereafter milling the thermosetmaterial.
 12. The method of claim 11, wherein the solvent is an organicsolvent selected from the group consisting of ethyl acetate andtetrahydrofuran.
 13. The method of claim 8 further comprising sizing theparticles of the thermoset material.
 14. The method of claim 13, whereinthe sizing comprises sieving.
 15. The method of claim 8, wherein thestep of forming particles comprises soaking the thermoset material in asolvent to dissolve low molecular weight fractions and thereafteragitating the thermoset material to crumble the thermoset material intothe particles.
 16. The method of claim 8, wherein the thermoset materialis doped with an active ingredient.
 17. The method of claim 8 furthercomprising curing a resin of PGS to form the thermoset material.
 18. Themethod of claim 17 further comprising loading the resin of PGS with anactive ingredient prior to curing the resin of PGS.